Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

• the invention relates to a multi-phase preparation containing substances with a contraceptive action in dosage units for oral administration having 22-30 dosage units in a specific sequence.
• Combination preparations of this type usually consist of 20-22 (usually 21) tablets of the same composition in respect of substances having a contraceptive action (e.g. progestogen and oestrogen or "estrogen").
• One tablet is taken daily, after which a tablet-free period of 5-7 days usually follows. This regimen coincides with the natural female menstrual cycle of about 28 days. Menstruation occurs in the tablet-free period. After the tablet-free period a new cycle is started with the combination preparation. If desired, placebos may be administered during the tablet-free period.
• placebo administration is that the daily administration of one tablet is not interrupted.
• Multi-phase contraceptive preparations with which different quantities of progestogen and/or oestrogen are used in different phases of the cycle are also known.
• a goal of the multi-phase contraceptive preparations is to achieve good control of the cycle while using smaller quantities of progestogen and/or oestrogen than are used in the monophase combination preparations.
• Two-phase preparations of the so-called sequential and "normophase" type are also known with which exclusively oestrogenis dosed during a first phase and a combination of a progestogen and an oestrogen is dosed during a second phase. See, for example, US-A-3,409,721 and US-A-3,502,772.
• the known multi-phase contraceptive preparations illustrate the development which has already been underway for some time to develop oral contraceptives having the aim of reducing as far as possible the possible side effects of "the pill”.
• Possible side effects of the pill include cardiovascular venous and non-venous disorders, including thrombosis and hypertension; increased weight; breast cancer, and cancer of the cervix.
• the lower limit for the total quantity of oestrogen per cycle would appear to be approximately 0.6 and 0.7 mg expressed in mg EE. If the oestrogen dose is too low, break-through bleeding and spotting take place, specifically in the second half of the cycle. These side effects could be countered by increasing the progestogen dose. However, the hormonal load on the body per unit time in the period in which active substances are administered becomes greater again.
• the lowering of the total hormonal load is essentially effected by the low progestogen dosage at the start of the cycle, which is also the most desirable from the standpoint of cycle control. In practice, however, such a lowering is found to be at the expense of reliability.
• Increasing the progestogen dose at the start of the cycle brings us back to the tried concept of the monophase preparation with a constant daily dose of the progestogen and oestrogen combination.
• a multi-phase contraceptive preparation having 22-30 dosage units has now been found which is a highly reliable contraceptive.
• the preparation includes at least two phases, the first of which consists of 20-22 dosage units which each contain both progestogen and oestrogen and a second phase having 2-10 dosage units which contain only progestogen as the active substance.
• the invention relates to a multi-phase preparation containing contraceptive substances in dosage units for oral administration having 22-30 dosage units in a specific sequence.
• One dosage unit is administered daily during treatment and the sequence is determined in advance by the manner in which the dosage units are packaged.
• the preparation includes at least two phases, the first of which consists of 20-22, preferably 21, sequential dosage units, which contain both progestogenic and oestrogenic substances. It is possible, if desired, for the first phase with dosage units of the combination type to contain various sub-phases with varying quantities of progestogen and/or oestrogen.
• the second phase consists of 2-10, preferably 7, sequential dosage units which contain only a progestogen as the active constituent, preferably in an amount per dosage unit which is lower than that in the last dosage unit of the first phase.
• the amount of progestogen in the dosage units of the second phase can (for practical reasons) be kept constant.
• the second phase can, if desired, also consist of sub-phases with varying quantities of progestogen.
• withdrawal bleeding will usually take place shortly afterwards because the oestrogen dosage is stopped. This bleeding may be delayed by several days, but this does not constitute an insurmountable drawback to starting with a new cycle of administration on the customary day in any case.
• all substances having a progestogenic action are suitable as the progestogen in the preparation according to the invention, such as, for example, lynestrenol, desogestrel, norethisterone, norethisterone acetate, ethynodiol diacetate, dl -norgestrel, d -norgestrel, gestoden, norgestimate, norethynodrel and cingestol, and derivatives thereof, which are obtained by introduction of one or more double bonds, for example in the 14(15)-position, by substitution, for example with chlorine or methyl in, for example, the 7- or 11-position, or by preparation of functional derivatives, such as, for example, esters, in particular esters of alkane carboxylic acids having 1-12 C atoms, ethers, such as alkyl(1-4 C) ethers or acetals, such as ethylene diacetals or propylenediacetals.
• desogestrel the 3-oxo-derivative of desogestrel, norgestimate, d-norgestrel or gestoden is used as progestogen.
• the greatest preference is, however, for desogestrel.
• the customary oestrogens can be used as oestrogen in the first phase (the combination phase) of the preparation according to the invention, for example EE, mestranol, oestradiol, oestradiol esters and substituted derivatives hereof.
• EE mestranol
• oestradiol oestradiol esters
• substituted derivatives hereof e.g. EE, mestranol, oestradiol, oestradiol esters and substituted derivatives hereof.
• the preference is for the orally effective oestradiol-17 ⁇ -esters, but in particular for oestradiol itself (E2), the naturally occurring "female" steroid.
• progestogen or oestrogen relate to quantities of desogestrel as progestogen and quantities of (17 ⁇ )-­oestradiol as oestrogen unless expressly stated otherwise. These are then, however, always understood as meaning a quantity of another progestogen or oestrogen which is equivalent in respect of progestational or oestrogenic action.
• progestogens and/or oestrogens can be used in the different phases in the preparation according to the invention.
• the quantity of progestogen in the tablets containing only a substance having a progestogenic action as the active constituent is usually between 0.020 mg and 0.125 mg, preferably between about 0.025 and about 0.050 mg.
• the quantity of progestogen per dosage unit in the second phase will preferably be lower the higher the number of dosage units and vice versa.
• the total quantity of progestogen in the second phase will be in the range between 0.120 mg and 0.250 mg.
• a practical quantity is, for example, 0.03 mg desogestrel per tablet for 6 or 7 tablets, which signifies a total quantity of 0.18-0.21 mg progestogen.
• the total quantity of progestogen per cycle will be in the range of 1.5-3.5 mg, the major portion (about 1.3-3.3 mg) being administered during the combination phase and the remainder (about 0.12-0.25 mg) during the second phase.
• the distribution over the various dosage units of the combination phase is constant or phased and in the latter case can be taken identical to that in known 2- or 3-phase combination preparations.
• the combination phase consists of several sub-phases, the progestogen content of the dosage units in each subsequent sub-phase being higher than that in the preceding sub-phase.
• the total quantity of oestrogen in the combination phase of the preparation according to the invention is in the range from about 30 mg to about 75 mg.
• a practical quantity is, for example, 2.0 mg oestradiol per dosage unit which signifies a total quantity of 42 mg.
• oral dosage units such as tablets, pills, capsules, dragees and granules.
• the oral dosage units are obtained by mixing the desired quantities of the progestogen and the oestrogen with the conventional pharmaceutically acceptable auxiliaries, such as fillers, binders, disintegrating agents, colourings, flavourings and lubricants, and bringing the mixture into the form of a pharmaceutical shaped product, or filling capsules with the mixture.
• auxiliaries such as fillers, binders, disintegrating agents, colourings, flavourings and lubricants
• a practical dosage form is the soft gelatin capsule, specifically in the case where an oestradiol 17 ⁇ -ester in a fluid lipoid substance, for example peanut oil or oleic acid, is used as the oestrogen.
• the active substances are then dissolved and/or dispersed in the lipoid fluid and the mixture is encapsulated in soft gelatin capsules in the conventional manner.
• the preparation according to the invention can be supplemented with a number of placebos to bridge the period in which no active substances are administered, so that a regular daily swallowing of a dosage unit does not have to be interrupted.
• days are indicated on the packs in which the preparation according to the invention is packaged, indicating at what time in the cycle the dosage unit corresponding to the indicated day must be taken.
• the preparation can be packaged in a tube or box or in a so-called strip pack.
• a box which can be round, rectangular or of another shape
• the dosage units are sealed therein separately, usually around the circumference of the box, a series of day indications, which may or may not be adjustable, corresponding to the days on which each of the dosage units must be taken being given on the box.
• strip pack or push-through pack
• day indications or other indications which indicate the sequence in which the dosage units must be taken are given on the strip or the pack.
• Example I was repeated except that the oestradiol 17 ⁇ -ester used in example Ia) was oestradiol 17 ⁇ -(2-­methyl)-decanoate in an amount of 7.936 g per litre, so that the capsules in the first phase contained, in addition to 0.150 mg desogestrol, 0.5 mg oestradiol 17 ⁇ -­(2-methyl)-decanoate.
• composition of tablets in the first phase (21 tablets) 0.150 mg desogestrel 2.000 mg 17 ⁇ -oestradiol 8.000 mg potato starch 2.400 mg polyvinylpyrrolidone 0.800 mg stearic acid 0.080 mg dl - ⁇ -tocopherol made up to 80.000 mg with lactose in the 2nd phase (7 tablets) 0.030 mg desogestrel 8.000 mg potato starch 2.400 mg polyvinylpyrrolidone 0.800 mg stearic acid 0.800 mg silica 0.080 mg dl - ⁇ -tocopherol made up to 80.000 mg with lactose.
• Example III is repeated except that 30 g EE is used in place of 2.00 mg 17 ⁇ -oestradiol.
• composition of tablets in the first phase (21 tablets) First sub-phase (7 tablets) 0.050 mg desogestrel 3.000 mg 17 ⁇ -oestradiol 8.000 mg potato starch 2.400 mg polyvinylpyrrolidone 0.800 mg stearic acid 0.800 mg silica 0.080 mg dl - ⁇ -tocopherol made up to 80.000 mg with lactose.
• Composition of tablets As in example V except that 0.035 mg EE is used in the first sub-phase and 0.030 mg EE is used in the second sub-phase.
• composition of tablets In the first phase (21 tablets) 1st sub-phase (7 tablets) 0.050 mg desogestrel 3.000 mg 17 ⁇ -oestradiol 8.000 mg potato starch 2.400 mg polyvinylpyrrolidone 0.800 mg stearic acid 0.800 mg silica 0.080 mg dl - ⁇ -tocopherol made up to 80.000 mg with lactose.
• 2nd sub-phase (7 tablets) 0.100 mg desogestrel 2.000 mg 17 ⁇ -oestradiol and in other respects identical to the composition in the first sub-phase; 3rd sub-phase (7 tablets) 0.150 mg desogestrel 1.500 mg 17 ⁇ -oestradiol and in other respects identical to the composition in the preceding sub-phases; in the 2nd phase (7 tablets) 0.030 mg desogestrel and in other respects identical to the composition in the preceding phases.
• Example VII the first phase, however, consisting of 22 tablets (by making the third sub-phase consist of 8 tablets) and the second phase consisting of 6 tablets.
• composition of dragees in the lst phase (21 dragees) 1st sub-phase (11 dragees) 0.050 mg d -norgestrel 2.000 mg 17 ⁇ -oestradiol 15.000 mg maize starch 2.000 mg polyvinylpyrrolidone 1.500 mg talc made up to 80.000 mg with lactose; 2nd sub-phase (10 dragees) 0.125 mg d-norgestrel 2.000 mg 17 ⁇ -oestradiol and in other respects identical to the composition in the first sub-phase; in the 2nd phase (2 dragees) 0.125 mg d-­norgestrel and in respect of auxiliaries identical to the composition in the preceding phases.
• Dragees which in respect of auxiliaries are identical to those in Example IX. 6 dragees: 0.050 mg d -norgestrel 2.000 mg 17 ⁇ -oestradiol 5 dragees: 0.075 mg d -norgestrel (1st phase) 2.500 mg 17 ⁇ -oestradiol 10 dragees: 0.125 mg d -norgestrel 2.000 mg 17 ⁇ -oestradiol 3 dragees: 0.070 mg d -norgestrel (2nd phase) 2 dragees 0.050 mg d -norgestrel
• Example X gestoden, however, being used in an equivalent amount in place of d -norgestrel.

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Cited By (6)

Citations (1)

• 1989
  • 1989-10-09 EP EP89202543A patent/EP0368373A1/fr not_active Withdrawn
  • 1989-10-11 NZ NZ230967A patent/NZ230967A/en unknown
  • 1989-10-11 CA CA002000438A patent/CA2000438A1/fr not_active Abandoned
  • 1989-10-12 KR KR1019890014611A patent/KR910007514A/ko not_active Application Discontinuation
  • 1989-10-12 DK DK507689A patent/DK507689A/da not_active Application Discontinuation
  • 1989-10-12 ZA ZA897749A patent/ZA897749B/xx unknown
  • 1989-10-13 AU AU42879/89A patent/AU628397B2/en not_active Ceased
  • 1989-10-13 JP JP1267974A patent/JPH02174717A/ja active Pending

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